The present invention relates to compositions and methods for preventing or reducing the risk or incidence of skeletal injuries in horses. The present invention further relates to compositions and methods for alleviating pain associated with skeletal injuries in horses and to treating skeletal injuries in horses. The present invention also relates to compositions and methods for treating or preventing glucocorticoid-induced bone loss in horses.
The horse industry in the U.S. produces goods and services valued at $25.3 billion in 1996 (American Horse Council, Washington, D.C.).
Skeletal injuries are a significant cause of death in performance horses, which are horses involved in activities such as racing, pacing, and other competitive events. The loss of a performance horse to such an injury can have a profound and far reaching effect. These injuries are not only distressing to the horse owners who often have a large emotional and financial commitment at stake, and also to spectators and other horse lovers. Furthermore, these injuries can also be extremely dangerous and even life threatening for jockeys, racers, and others.
In California alone, between 150 and 200 horses die or are euthanized each year as a result of catastrophic bone injury due to racing or training. See Estberg, et al., Preventative Vet. Med. 33: 159-170, 1998, which is incorporated by reference herein in its entirety. In addition to ethical and humane considerations, there is a very strong financial incentive to properly care for and prevent and reduce the risk or incidence of skeletal injuries in horses.
The performance horse, such as a racehorse, is an athlete capable of reaching and sustaining high training and racing speeds. Under these conditions, great demands are placed on the weight-bearing structures of the musculoskeletal system. Injuries can often occur abruptly during exercise. Injuries can also be caused by chronic skeletal damage incurred while training and performing or by skeletal atrophy due to nonexercise and forced stall rest. Skeletal atrophy and bone loss is characterized by conditions such as osteoporosis or osteopenia. These conditions are characterized by a decrease in bone mass density and by microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. These undesired skeletal changes can occur relatively rapidly after only a few weeks of inactivity and raises concerns about the common practice of stall rest such as the housing of yearling horses in stalls prior to yearling sales or prior to the commencement of training. Furthermore, the necessity of submitting injured or sick horses to forced stall rest raises concerns about how best to return such horses to activity without causing injury.
Normal bone physiology involves a process wherein bone tissue is continuously being turned over by the processes of modeling and remodeling. In other words, there is normally an appropriate balance between resorption of existing bone tissue and the formation of new bone tissue. The exact mechanism underlying the coupling between bone resorption and formation is still unknown. However, an imbalance in these processes is manifested in various disease states and conditions of the skeleton.
Two different types of cells called osteoblasts and osteoclasts are involved in the bone formation and resorption processes, respectively. See H. Fleisch, Bisphosphonates In Bone Disease, From The Laboratory To The Patient, 4th Edition, Parthenon Publishing (2000), which is incorporated by reference herein in its entirety.
Studies from the California Racetrack necroscopy studies indicate that fatal catastrophic musculoskeletal injuries in horses, principally fractures of proximal seamoid, third metacarpus and humerus, occur at an incidence of 1.7 per 1000 starts. See Estberg, L. et al., xe2x80x9cFatal musculoskeletal injuries incurred during racing and training in thoroughbredsxe2x80x9d, Journal of the American Veterinary Medical Association, 208(1): 92-96 (Jan. 1, 1996), which is incorporated by reference herein in its entirety. This is in general agreement with data from other studies (New York 1.1 per 1000 starts; Minnesota and Illinois-1.8; Japan-3.2; Kentucky-1.4, South Africa 1.4; Australia 0.3) cited by Mundy, Proc. Annual Conference of American Association of Equine Practioners, 204-220 (1997), which is also incorporated by reference herein in its entirety. The incidence of non-fatal injuries, horses which develop an abnormal gait or which require the ambulance to attend to a horse occur at rates 3-7 times higher than these catastrophic injuries.
Horses returning to racing following a lay-up (spelling) period, greater than 60 days without a race or fast time work, are 70 times more likely to suffer a fatal humeral fracture. Sixty-five percent of these incidents occur within 10 days of a lay-up. It is speculated that the spelling period predisposes the horses to disuse osteoporotic change to these long bones Carrier et al. 1998.
Buckingham, S. H. W. et al., xe2x80x9cOsteopenic effects of forelimb immobilization in horsesxe2x80x9d, Veterinary Record, 128: 370-373 (1991), which is incorporated by reference herein in its entirety, demonstrated that immobilization of a forelimb of horses by applying a cast for 8 weeks caused loss of bone strength and mineral content from both limbs but was more pronounced in the leg with the cast.
The following references, which are all incorporated by reference herein in their entirety, provide additional background on the subject of skeletal injuries of horses:
Porr, C. A. et al., xe2x80x9cDeconditioning Reduces Mineral Content of the Third Metacarpal Bone in Horsesxe2x80x9d, Journal of Animal Science, 76: 1875-1879 (1998).
Johnson, B. J. et al., xe2x80x9cCauses of death in racehorses over a 2 year periodxe2x80x9d, Equine Veterinary Journal, 26(4): 327-330 (1994).
Estberg, L. et al., xe2x80x9cRelationship between race start characteristics and risk of catastrophic injury in thoroughbreds: 78 cases (1992)xe2x80x9d, Journal of the American Veterinary Medical Association, 212(4): 544-549 (Feb. 15, 1998).
Hoekstra, K. E. et al., xe2x80x9cStalling Young Horses Alters Normal Bone Growthxe2x80x9d, Association for Equine Sports Medicine Proceedings, AGM, Leesburg, Va. (1998).
Carrier, T. K. et al., xe2x80x9cAssociation between long periods without high-speed workouts and risk of complete humeral or pelvic fracture in thoroughbred racehorses; 54 cases (1991-1994)xe2x80x9d, Journal of the American Veterinary Medical Association, 212(10): 1582-1587 (May 15, 1998).
Estberg, L. et al., xe2x80x9cHigh-speed exercise history and catastrophic racing fracture in thoroughbredsxe2x80x9d, American Journal of Veterinary Research, 57(11):1549-1555 (Nov. 1996).
Lepage, O. M. et al., xe2x80x9cL""emploi d""un bisphosphonate (APD) dans la prevention des exoxtoses chez le poney Shetland. Eutde preliminaire. Ann Med. Vet., 132:391-399 (1988).
Lepage, O. M. et al., xe2x80x9cAspects microradiographiques et en microscopie de fluorescence d""une exotose experimentale du metacarpein chez le poney Shetland et de son traitement par un bisphosphonate, Lxe2x80x9dAhpfBP (APD). Applications possible aucheval d""armexe2x80x9d, Annales Medicinae Militaris Belgicase 3(2):38-44 (1989).
Estberg, L. et al., xe2x80x9cA cross over study of intensive racing and training schedules and risk of catastrophic musculoskeletal injury and lay-up in California thoroughbred racehorsesxe2x80x9d, Preventative Vet. Med., 33: 159-170 (1998).
The skeletal injuries and underlying predisposing conditions are to be distinguished from navicular disease in horses. The navicular bone is a boat-shaped bone located at the medial side of the tarsus. Navicular disease is a specific disorder of this bone, causing lameness and frequently leading to loss of function in a performance horse. Without being limited by theory, the pathophysiology of this disease is not well defined but it is thought to be related to blood circulation through the foot and particularly to the navicular bone. Disruption to this blood supply leads to physical changes in the bone, causing pain. Navicular disease is a specific condition, affecting this bone only, and there is no evidence that circumstances which cause generalized bone resorption predispose to the development of navicular disease. PCT patent application number WO 97/12619, to Novartis, published Apr. 10, 1997 describes the use of various bisphosphonates in the treatment of navicular disease in horses. However, there is no teaching of the methods of the present invention. In contrast the present invention relates to composition and methods for preventing or reducing the risk of incidence of skeletal injuries in horses, i.e. conditions relating to abnormal or undesired changes in the bone resorption/formation balance, rather than to circulatory disorders associated with one specific bone.
Currently, there is no totally satisfactory means for preventing or reducing the risk or incidence of skeletal injuries in horses, nor to alleviating pain associated with skeletal injuries or to treating skeletal injuries.
Bisphosphonates are known in the art to bond to hydroxyapatite in bone and to inhibit the bone resorptive activity of osteoclasts. See H. Fleisch, Id. For example, bisphosphonates are known to be useful in the treatment of such diseases as osteoporosis, hypercalcemia of malignancy, osteopenia due to bone metastases, periodontal disease, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, Paget""s disease, immobilization-induced osteopenia, and glucocorticoid-induced osteoporosis. All of these conditions are characterized by bone loss, resulting from an imbalance between bone resorption, i.e. breakdown, and bone formation. Even though bisphosphonates have been used to treat the above-mentioned diseases, there is little evidence of their use for preventing or reducing the risk or incidence of skeletal injuries in horses or for alleviating pain associated with skeletal injuries or for treating skeletal injuries. At most there is the methods associated with the localized specific condition of navicular disease. Also, there are the specific limited studies on Shetland ponies where a bisphosphonate was used to reduce the size of exostoses induced by an experimental surgical lifting of the periosteum. Without being limited by theory, this application of a bisphosphonate falls outside the present discovery since the development of exostosis in response to a periosteal injury is not a disease/injury resulting from excessive bone resorption.
In addition to the above discussion, it is well-known that glucocorticoid use can result in bone loss in humans. These powerful drugs, such as prednisone or dexamethasone, are commonly used to treat the pain and inflammation associated with the activities of high performance horses. There is strong evidence that the use of these drugs in such horses can lead to bone loss and accompanying complications. There is thus a need to treat or prevent glucorticoid bone-loss, and its attendend conditions such as osteopenia and osteoporosis in horses.
It is surprisingly been found in the present invention that bisphosphonates are effective for preventing or reducing the risk or incidence of skeletal injuries in horses and for alleviating pain associated with skeletal injuries and for treating skeletal injuries.
It is an object of the present invention to provide a method of preventing or reducing the risk or incidence of skeletal injuries in horses comprising administering a therapeutically effective amount of a bisphosphonate or a pharmaceutically acceptable salt thereof or ester thereof or mixtures thereof.
It is another object of the present invention to provide a method of alleviating pain associated with skeletal injuries in horses comprising administering a therapeutically effective amount of a bisphosphonate or a pharmaceutically acceptable salt thereof or ester thereof or mixtures thereof.
It is another object of the present invention to provide a method of treating skeletal injuries in horses comprising administering a therapeutically effective amount of a bisphosphonate or a pharmaceutically acceptable salt thereof or ester thereof or mixtures thereof.
It is another object of the present invention to provide a method of treating or preventing glucocorticoid-induced bone loss in horses comprising administering a therapeutically effective amount of a bisphosphonate or a pharmaceutically acceptable salt thereof or ester thereof or mixture thereof.
It is another object of the present invention to provide the use of a bisphosphonate or a pharmaceutically acceptable salt thereof or ester thereof or mixture thereof for preventing or reducing the risk or incidence of skeletal injuries in horses.
It is another object of the present invention to provide the use of a bisphosphonate or a pharmaceutically acceptable salt thereof or ester thereof or mixture thereof for alleviating pain associated with skeletal injuries in horses.
It is another object of the present invention to provide the use of a bisphosphonate or a pharmaceutically acceptable salt thereof or ester thereof or mixture thereof for treating skeletal injuries in horses.
It is another object of the present invention to provide the use of a bisphosphonate or a pharmaceutically acceptable salt thereof or ester thereof or mixture thereof for treating or preventing glucocorticoid-induced bone loss in horses.
It is another object of the present invention to provide the use of a bisphosphonate or a pharmaceutically acceptable salt thereof or ester thereof or mixture thereof in the manufacture of a medicament for preventing or reducing the risk or incidence of skeletal injuries in horses.
It is another object of the present invention to provide the use of a bisphosphonate or a pharmaceutically acceptable salt thereof or ester thereof or mixture thereof in the manufacture of a medicament for alleviating pain associated with skeletal injuries in horses.
It is another object of the present invention to provide the use of a bisphosphonate or a pharmaceutically acceptable salt thereof or ester thereof or mixture thereof in the manufacture of a medicament for treating skeletal injuries in horses.
It is another object of the present invention to provide the use of a bisphosphonate or a pharmaceutically acceptable salt thereof or ester thereof or mixture thereof in the manufacture of a medicament for treating or preventing glucocorticoid-induced bone loss in horses.
It is another object of the present invention to provide a pharmaceutical composition for preventing or reducing the risk or incidence of skeletal injuries in horses comprising a therapeutically effective amount of a bisphosphonate or a pharmaceutically acceptable salt thereof or ester thereof or mixture thereof.
It is another object of the present invention to provide a pharmaceutical composition for alleviating pain associated with skeletal injuries in horses comprising a therapeutically effective amount of a bisphosphonate or apharmaceutically acceptable salt thereof or ester thereof or mixture thereof.
It is another object of the present invention to provide a pharmaceutical composition for treating skeletal injuries in horses comprising a therapeutically effective amount of a bisphosphonate or a pharmaceutically acceptable salt thereof or ester thereof or mixture thereof.
It is another object of the present invention to provide pharmaceutical compositions for treating or preventing glucocorticoid-induced bone loss in horses comprising a therapeutically effective amount of a bisphosphonate or a pharmaceutically acceptable salt thereof or ester thereof or mixture thereof.
These and other objects will become readily apparent from the detailed description which follows.
The present invention relates to a method of preventing or reducing the risk or incidence of skeletal injuries in horses comprising administering a therapeutically effective amount of a bisphosphonate or a pharmaceutically acceptable salt thereof or ester thereof or mixtures thereof.
The present invention also relates to a method of alleviating pain associated with skeletal injuries in horses comprising administering a therapeutically effective amount of a bisphosphonate or a pharmaceutically acceptable salt thereof or ester thereof or mixture thereof.
The present invention also relates to a method for treating skeletal injuries in horses comprising administering a therapeutically effective amount of a bisphosphonate or a pharmaceutically acceptable salt thereof or ester thereof or mixture thereof.
The present invention also relates to a method for treating or preventing glucocorticoid-induced bone loss in horses comprising administering a therapeutically effective amount of a bisphosphonate or a pharmaceutically acceptable salt thereof or ester thereof or mixture thereof.
The present invention also relates to the use of a bisphosphonate or a pharmaceutically acceptable salt thereof or ester thereof or mixture thereof for preventing or reducing the risk or incidence of skeletal injuries in horses.
The present invention also relates to the use of a bisphosphonate or a pharmaceutically acceptable salt thereof or ester thereof or mixture thereof for alleviating pain associated with skeletal injuries in horses.
The present invention also relates to the use of a bisphosphonate or a pharmaceutically acceptable salt thereof or ester thereof or mixture thereof for treating skeletal injuries in horses.
The present invention also relates to the use of a bisphosphonate or a pharmaceutically acceptable salt thereof or ester thereof or mixture thereof for treating or preventing glucocorticoid-induced bone loss in horses.
The present invention also relates to the use of a bisphosphonate or a pharmaceutically acceptable salt thereof or ester thereof or mixture thereof in the manufacture of a medicament for preventing or reducing the risk or incidence of skeletal injuries in horses.
The present invention also relates to the use of a bisphosphonate or a pharmaceutically acceptable salt thereof or ester thereof or mixture thereof in the manufacture of a medicament for alleviating pain associated with skeletal injuries in horses.
The present invention also relates to the use of a bisphosphonate or a pharmaceutically acceptable salt thereof or ester thereof or mixture thereof in the manufacture of a medicament for treating or preventing glucocorticoid-induced bone loss in horses.
The present invention also relates to the use of a bisphosphonate or a pharmaceutically acceptable salt thereof or ester thereof or mixture thereof in the manufacture of a medicament for treating skeletal injuries in horses.
The present invention also relates to a pharmaceutical composition for preventing or reducing the risk or incidence of skeletal injuries in horses comprising a therapeutically effective amount of a bisphosphonate or a pharmaceutically acceptable salt thereof or ester thereof or mixture thereof.
The present invention also relates to a pharmaceutical composition for alleviating pain associated with skeletal injuries in horses comprising a therapeutically effective amount of a bisphosphonate or a pharmaceutically acceptable salt thereof or ester thereof or mixture thereof.
The present invention also relates to a pharmaceutical composition for treating or preventing glucocorticoid-induced bone loss in horses comprising a therapeutically effective amount of a bisphosphonate or a pharmaceutically acceptable salt thereof or ester thereof or mixture thereof.
The present invention also relates to a pharmaceutical composition for treating skeletal injuries in horses comprising a therapeutically effective amount of a bisphosphonate or a pharmaceutically acceptable salt thereof or ester thereof or mixture thereof.
All percentages and ratios used herein, unless otherwise indicated, are by weight. The invention hereof can comprise, consist of, or consist essentially of the essential as well as optional ingredients, components, and methods described herein.